There are about 5.3 million people in this country living with a range of disabilities caused by traumatic brain injury, and about 25-30% of those people are unable to return to work one year later. At present, there are no effective clinical treatments currently available to the victims of traumatic brain injuries that can repair the primary and secondary damage caused by the cascade of cytotoxic damage unleashed by the initial insult. Obviously, a safe, low cost and effective treatment for such a significant health problem is worth addressing. Numerous reports have documented the role of neurosteroids in immediate post-injury neuroprotection. However, few studies have examined the effect of these steroids as a treatment after the acute phase. We are particularly interested in the effect of progesterone long-term because it is currently being tested in a human clinical trial as an acute phase neuroprotectant. Extensive preclinical trials have shown that progesterone is neuroprotective when administered shortly after injury. However, at least two of the potential mechanisms (inhibition of NMDA transmission and stimulation of GABAA receptors), by which progesterone exhibits neuroprotection, could potentially worsen subacute rehabilitation and subsequent long-term recovery. Conversely, pregnenolone, the precursor of progesterone, exhibits opposite effects with respect to NMDA and GABAA modulation and could enhance neurorehahilitation. We propose to determine the effects of progesterone and pregnenolone when treatment is delayed after injury in animals. The data gathered would provide information regarding the potential utility of these neurosteroids in subacute or long-term treatment conditions. In addition, should progesterone prove to be an effective neuroprotectant in the human clinical trial, it will be necessary to know how long treatment should be maintained and whether long-term treatment enhances or deters post-injury rehabilitation. There is a growing body of evidence that both progesterone and pregnenolone can also stimulate remyelination of damaged nerve cells and that they also have the potential to stimulate neuronal repair after the initial injury cascade has long subsided. This means that these steroids, both of which are synthesized in the brain, may be beneficial as adjunct therapies for long-term rehabilitation. We propose to investigate the role of the neurosteroids progesterone (PROG) and pregnenolone-sulfate (PREGS) as putative treatment for traumatic brain injury during the rehabilitation phase of recovery in both male and female subjects. Therefore, we will examine two delayed treatment paradigms (7 days & 28 days post injury) on the recovery process at the behavioral and morphological levels of analysis.